Novel pharmaceutical formulations

ABSTRACT

The present invention relates to new extended release pharmaceutical compositions and methods of use thereof for the treatment of disorders.

This application is a continuation of U.S. Patent Application No.16/938,315, filed Jul. 24, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/177,516, filed Nov. 1, 2018, which is acontinuation of U.S. patent application Ser. No. 15/116,970, filed Aug.5, 2016, now U.S. Pat. No. 10,166,183, which is the national stageapplication filed under 35 U.S.C. § 371 of International PatentApplication No. PCT/US2015/014545, filed Feb. 5, 2015, which claims thebenefit of the priority of U.S. Provisional Patent Application Nos.61/937,189, filed Feb. 7, 2014, and 61/990,061, filed May 7, 2014, thedisclosures of which are hereby incorporated by reference as if writtenherein in their entireties.

Disclosed herein are new pharmaceutical compositions, formulations, andmethods of use thereof for the treatment of disorders.

The administration of various drugs can be complicated by unfavorablepharmacodynamic and/or pharmacokinetic properties such as poorabsorption or low bioavailability, short half-life or T_(max), highmaximal plasma concentration, low minimal plasma concentrations, orunfavorable food effects.

Thus, there is a need to develop extended release pharmaceuticalformulations that provide improved drug delivery properties, such asincreased half-life, increased T_(max), reduced C_(max) and/ordose-normalized C_(max), while maintaining acceptable bioavailabilityand moderate food effects.

Novel pharmaceutical compositions have been discovered, together withmethods of synthesizing and using the compositions, including methodsfor the treatment of disorders in a patient by administering thecompositions as disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Method of preparation of tetrabenazine extended releaseformulations.

FIG. 2: Dimensions of Gastro-Retentive Extended Release Large Tablet.

In certain embodiments, disclosed herein is an extended-releasepharmaceutical formulation comprising, in a solid dosage form for oraldelivery of between about 100 mg and about 1 g total weight:

between about 2 and about 18% of an active ingredient;

between about 70% and about 96% of one or more diluents;

between about 1% and about 10% of a water-soluble binder; and

between about 0.5 and about 2% of a surfactant.

In certain embodiments, the diluent or diluents are chosen frommannitol, lactose, and microcrystalline cellulose; the binder is apolyvinylpyrrolidone; and the surfactant is a polysorbate.

In certain embodiments, the extended-release pharmaceutical formulationcomprises between about 2.5% and about 11% of an active ingredient.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 60% and about 70% mannitol or lactose;

between about 15% and about 25% microcrystalline cellulose

about 5% of polyvinylpyrrolidone 1(29/32; and

between about 1 and about 2% of Tween 80.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 4% and about 9% of an active ingredient;

between about 60% and about 70% mannitol or lactose;

between about 20% and about 25% microcrystalline cellulose

about 5% of polyvinylpyrrolidone K29/32; and

about 1.4% of Tween 80.

In certain embodiments, disclosed herein is an extended-releasepharmaceutical formulation comprising, in a solid dosage form for oraldelivery of between about 100 mg and about 1 g total weight:

between about 70 and about 95% of a granulation of an active ingredient,wherein the active ingredient comprises between about 1 and about 15% ofthe granulation;

between about 5% and about 15% of one or more diluents;

between about 5% and about 20% of sustained-release polymer; and

between about 0.5 and about 2% of a lubricant.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 5% and about 15% of one or more spray-dried mannitol orspray-dried lactose;

between about 5% and about 20% of sustained-release polymer; and

between about 0.5 and about 2% of a magnesium stearate.

In certain embodiments, the sustained-release polymer is chosen from apolyvinyl acetate-polyvinylpyrrolidone mixture and a poly(ethyleneoxide) polymer.

In certain embodiments, the sustained-release polymer is chosen fromKollidon® SR, POLYOX® N60K, and Carbopol®.

In certain embodiments, the sustained-release polymer is Kollidon® SR.

In certain embodiments, the sustained-release polymer is POLYOX® N60K.

In certain embodiments, the sustained-release polymer is Carbopol®.

In certain embodiments, the extended-release pharmaceutical formulationcomprises from about 5 mg to about 250 mg of an active ingredient.

In certain embodiments, the active ingredient is selected from the groupconsisting of tetrabenazine, dihydrotetrabenazine, ketamine,pirfenidone, phenylephrine, ethambutol, venlafaxine, zolipidem,esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole,sitaxentan, codeine, hydrocodone, morphine, oxycodone, almotriptan,eletriptan, naratriptan, sumatriptan, zolmitriptan, ranolazine,desmethylvenlafaxine, mirabegron, ticagrelor, darapladib, rilapladib,nilotinib, tofacitinib, apixaban, lumiracoxib, solabegron, riociguat,cariprazine, neratinib, pelitinib, fostamatinib, R-406,dihydrotetrabenazine, NBI-98854, nintedanib, F-351, agomelatine,almorexant, alogliptin, anastrozole, aripiprazole, atomoxetine,bosentan, brivaracetam, bupropion, cediranib, cinacalcet, clemizole,dextromethorphan, dimeboline, donepezil, duloxetine, fingolimod,gefitinib, imatinib, ITMN-191, ivabradine, linezolid, lonafarnib,maraviroc, mosapride, nateglinide, oxybutynin, paroxetine, pazopanib,quetiapine, rilpivirine, rimonabant, rolofylline, sitagliptin,tolterodine, udenafil, valproic acid, vandetanib, vildagliptin,alpha-lipoic acid, ambrisentan, anacetrapib, apremilast, atazanavir,bardoxolone, baricitinib, boceprevir, brecanavir, carfilzomib, carmofur,cilostazol, conivaptan, crizotinib, darunavir, dasatinib,dimethylcurcumin, dolutegravir, elvitegravir, erlotinib, etravirine,felbamate, filibuvir, gliclazide, ibudilast, ibrutinib, idebenone,iloperidone, iloprost, indiplon, ivacaftor, L-838417, lacosamide,lapatinib, lenalidomide, lorcaserin, mibefradil, milnacipran, N-butylbumetanide, NTP-2014, niacin, niacin prodrugs, NS11394, NS-304, MRE-304,MRE-269, pagoclone, pentifylline, pentoxifylline, pentoxifyllinemetabolites, PLX4032, pomalidomide, ponatinib, PPL-100, praziquantel,preladenant, primaquine, radequinil, raltegravir, rigosertib,rivaroxaban, ruxolitinib, safinamide, silodosin, sodium oxybate,4-hydroxybutyrate, sorafenib, telcagepant, thalidomide, tigecycline,omadacycline, tizanidine, TPA-023, treprostinil, varespladib, vercirnon,vicriviroc, levodopa, carbidopa, levodopa in combination with carbidopa,amantadine, dipraglurant, nintedanib, and pridopidine.

In certain embodiments, the active ingredient is selected from the groupconsisting of a deuterated analog of tetrabenazine, a deuterated analogof dihydrotetrabenazine, a deuterated analog of ketamine, a deuteratedanalog of pirfenidone, a deuterated analog of phenylephrine, adeuterated analog of ethambutol, a deuterated analog of venlafaxine, adeuterated analog of zolipidem, a deuterated analog of esomeprazole, adeuterated analog of lansoprazole, a deuterated analog of omeprazole, adeuterated analog of pantoprazole, a deuterated analog of rabeprazole, adeuterated analog of sitaxentan, a deuterated analog of codeine, adeuterated analog of hydrocodone, a deuterated analog of morphine, adeuterated analog of oxycodone, a deuterated analog of almotriptan, adeuterated analog of eletriptan, a deuterated analog of naratriptan, adeuterated analog of sumatriptan, a deuterated analog of zolmitriptan, adeuterated analog of ranolazine, a deuterated analog ofdesmethylvenlafaxine, a deuterated analog of mirabegron, a deuteratedanalog of ticagrelor, a deuterated analog of darapladib, a deuteratedanalog of rilapladib, a deuterated analog of nilotinib, a deuteratedanalog of tofacitinib, a deuterated analog of apixaban, a deuteratedanalog of lumiracoxib, a deuterated analog of solabegron, a deuteratedanalog of riociguat, a deuterated analog of cariprazine, a deuteratedanalog of neratinib, a deuterated analog of pelitinib, a deuteratedanalog of fostamatinib, a deuterated analog of R-406, a deuteratedanalog of dihydrotetrabenazine, a deuterated analog of NBI-98854, adeuterated analog of nintedanib, a deuterated analog of F-351, adeuterated analog of agomelatine, a deuterated analog of almorexant, adeuterated analog of alogliptin, a deuterated analog of anastrozole, adeuterated analog of aripiprazole, a deuterated analog of atomoxetine, adeuterated analog of bosentan, a deuterated analog of brivaracetam, adeuterated analog of bupropion, a deuterated analog of cediranib, adeuterated analog of cinacalcet, a deuterated analog of clemizole, adeuterated analog of dextromethorphan, a deuterated analog ofdimeboline, a deuterated analog of donepezil, a deuterated analog ofduloxetine, a deuterated analog of fingolimod, a deuterated analog ofgefitinib, a deuterated analog of imatinib, a deuterated analog ofITMN-191, a deuterated analog of ivabradine, a deuterated analog oflinezolid, a deuterated analog of lonafarnib, a deuterated analog ofmaraviroc, a deuterated analog of mosapride, a deuterated analog ofnateglinide, a deuterated analog of oxybutynin, a deuterated analog ofparoxetine, a deuterated analog of pazopanib, a deuterated analog ofquetiapine, a deuterated analog of rilpivirine, a deuterated analog ofrimonabant, a deuterated analog of rolofylline, a deuterated analog ofsitagliptin, a deuterated analog of tolterodine, a deuterated analog ofudenafil, a deuterated analog of valproic acid, a deuterated analog ofvandetanib, a deuterated analog of vildagliptin, a deuterated analog ofalpha-lipoic acid, a deuterated analog of ambrisentan, a deuteratedanalog of anacetrapib, a deuterated analog of apremilast, a deuteratedanalog of atazanavir, a deuterated analog of bardoxolone, a deuteratedanalog of baricitinib, a deuterated analog of boceprevir, a deuteratedanalog of brecanavir, a deuterated analog of carfilzomib, a deuteratedanalog of carmofur, a deuterated analog of cilostazol, a deuteratedanalog of conivaptan, a deuterated analog of crizotinib, a deuteratedanalog of darunavir, a deuterated analog of dasatinib, a deuteratedanalog of dimethylcurcumin, a deuterated analog of dolutegravir, adeuterated analog of elvitegravir, a deuterated analog of erlotinib, adeuterated analog of etravirine, a deuterated analog of felbamate, adeuterated analog of filibuvir, a deuterated analog of gliclazide, adeuterated analog of ibudilast, a deuterated analog of ibrutinib, adeuterated analog of idebenone, a deuterated analog of iloperidone, adeuterated analog of iloprost, a deuterated analog of indiplon, adeuterated analog of ivacaftor, a deuterated analog of L-838417, adeuterated analog of lacosamide, a deuterated analog of lapatinib, adeuterated analog of lenalidomide, a deuterated analog of lorcaserin, adeuterated analog of mibefradil, a deuterated analog of milnacipran, adeuterated analog of N-butyl bumetanide, a deuterated analog ofNTP-2014, a deuterated analog of niacin, a deuterated analog of niacinprodrugs, a deuterated analog of NS11394, a deuterated analog of NS-304,a deuterated analog of MRE-304, a deuterated analog of MRE-269, adeuterated analog of pagoclone, a deuterated analog of pentifylline, adeuterated analog of pentoxifylline, a deuterated analog ofpentoxifylline metabolites, a deuterated analog of PLX4032, a deuteratedanalog of pomalidomide, a deuterated analog of ponatinib, a deuteratedanalog of PPL-100, a deuterated analog of praziquantel, a deuteratedanalog of preladenant, a deuterated analog of primaquine, a deuteratedanalog of radequinil, a deuterated analog of raltegravir, a deuteratedanalog of rigosertib, a deuterated analog of rivaroxaban, a deuteratedanalog of ruxolitinib, a deuterated analog of safinamide, a deuteratedanalog of silodosin, a deuterated analog of sodium oxybate, a deuteratedanalog of 4-hydroxybutyrate, a deuterated analog of sorafenib, adeuterated analog of telcagepant, a deuterated analog of thalidomide, adeuterated analog of tigecycline, a deuterated analog of omadacycline, adeuterated analog of tizanidine, a deuterated analog of TPA-023, adeuterated analog of treprostinil, a deuterated analog of varespladib, adeuterated analog of vercirnon, a deuterated analog of vicriviroc, adeuterated analog of levodopa, a deuterated analog of carbidopa, adeuterated analog of levodopa in combination with a deuterated analog ofcarbidopa, a deuterated analog of amantadine, a deuterated analog ofdipraglurant, a deuterated analog of nintedanib, a deuterated analog ofpridopidine, CTP-354, CTP-499, AVP-786, JZP-386, and CTP-730.

In certain embodiments, the active ingredient is

In certain embodiments, the active ingredient is

In certain embodiments, the active ingredient is

In certain embodiments, the active ingredient is selected from the groupconsisting of tetrabenazine, dihydrotetrabenazine, ketamine, adeuterated analog of ketamine, pirfenidone, and a deuterated analog ofpirfenidone.

In certain embodiments, the active ingredient is ketamine.

In certain embodiments, the active ingredient is a deuterated analog ofpirfenidone.

In certain embodiments, the active ingredient is pirfenidone.

In certain embodiments, the active ingredient is a deuterated analog ofpirfenidone.

In certain embodiments, disclosed herein is a method of treating adisease comprising the administration of the extended releasepharmaceutical composition as recited in claim 1, wherein thedose-normalized C_(max) of the active ingredient resulting from theadministration of the extended-release formulation is lower than thedose-normalized C_(max) resulting from the administration of theimmediate release formulated or unformulated active ingredient.

In certain embodiments, the ratio of extended release formulated C_(max)to immediate release formulated or unformulated C_(max) is less than 1.

In certain embodiments, the ratio of extended release formulated C_(max)to immediate release formulated or unformulated C_(max) is less thanabout 0.9.

In certain embodiments, the ratio of extended release formulated C_(max)to immediate release formulated or unformulated C_(max) is less thanabout 0.8.

In certain embodiments, the ratio of extended release formulated C_(max)to immediate release formulated or unformulated C_(max) is less thanabout 0.7.

In certain embodiments, the ratio of extended release formulated C_(max)to immediate release formulated or unformulated C_(max) is less thanabout 0.5.

In certain embodiments, disclosed herein is a method of treating adisease comprising the administration of the extended releasepharmaceutical composition as recited in claim 1, wherein the T_(max) ofthe active ingredient resulting from the administration of theextended-release formulation occurs later than the T_(max) resultingfrom the administration of the immediate release formulated orunformulated active ingredient.

In certain embodiments, the ratio of immediate release formulated orunformulated T_(max) to extended release formulated T_(max) is less than1.

In certain embodiments, the ratio of immediate release formulated orunformulated T_(max) to extended release formulated T_(max) is less thanabout 0.75.

In certain embodiments, the ratio of immediate release formulated orunformulated T_(max) to extended release formulated T_(max) is less thanabout 0.5.

In certain embodiments, the ratio of immediate release formulated orunformulated T_(max) to extended release formulated T_(max) is less thanabout 0.25.

In certain embodiments, disclosed herein is a method of treating adisease comprising the administration of the extended releasepharmaceutical composition as recited in claim 1 with food, wherein theratio of fed to fasted C_(max) of the total combined amount of theactive ingredient is greater than 1.

In certain embodiments, the ratio of fed to fasted C_(max) is greaterthan about 1.5.

In certain embodiments, the ratio of fed to fasted C_(max) is greaterthan about 2.0.

In certain embodiments, disclosed herein is a method of treating adisease comprising the administration of the extended releasepharmaceutical composition as recited in claim 1, wherein the ratio offed to fasted AUC_(inf) of the active ingredient is greater than 1.

In certain embodiments, the ratio of fed to fasted AUC_(inf) is greaterthan about 1.1.

In certain embodiments, the ratio of fed to fasted AUC_(inf) is greaterthan about 1.2.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of the extendedrelease pharmaceutical composition as recited in claim 1 with food,wherein the ratio of fed to fasted AUC_(t) of the active ingredient isgreater than 1.

In certain embodiments, the ratio of fed to fasted AUC_(t) is greaterthan about 1.1.

In certain embodiments, the ratio of fed to fasted AUC_(t) is greaterthan about 1.2.

In certain embodiments, disclosed herein is an extended-releasepharmaceutical formulation comprising, in a solid dosage form for oraldelivery of between about 100 mg and about 1 g total weight:

between about 2 and about 18% of tetrabenazine or dihydrotetrabenazine;

between about 70% and about 96% of one or more diluents;

between about 1% and about 10% of a water-soluble binder; and

between about 0.5 and about 2% of a surfactant.

In certain embodiments, the total weight is about 350 mg and about 750mg. In certain embodiments, the diluent or diluents are chosen frommannitol, lactose, and microcrystalline cellulose; the binder is apolyvinylpyrrolidone; and the surfactant is a polysorbate.

In certain embodiments, the extended-release pharmaceutical formulationcomprises between about 2.5% and about 11% of tetrabenazine ordihydrotetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 60% and about 70% mannitol or lactose;

between about 15% and about 25% microcrystalline cellulose

about 5% of polyvinylpyrrolidone 1(29/32; and

between about 1 and about 2% of Tween 80.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 4% and about 9% of a tetrabenazine ordihydrotetrabenazine;

between about 60% and about 70% mannitol or lactose;

between about 20% and about 25% microcrystalline cellulose

about 5% of polyvinylpyrrolidone K29/32; and

about 1.4% of Tween 80.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 7.5, 12.5 mg, 15 mg, 25 mg, 30 mg, and 50 mg oftetrabenazine or dihydrotetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises, in a solid dosage form for oral delivery of between about 100mg and about 1 g total weight:

between about 70 and about 95% of a granulation of tetrabenazine ordihydrotetrabenazine, wherein the tetrabenazine or dihydrotetrabenazinecomprises between about 1 and about 15% of the granulation;

between about 5% and about 15% of one or more diluents;

between about 5% and about 20% of sustained-release polymer; and

between about 0.5 and about 2% of a lubricant.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 5% and about 15% of one or more spray-dried mannitol orspray-dried lactose;

between about 5% and about 20% of sustained-release polymer; and

between about 0.5 and about 2% of a magnesium stearate.

In certain embodiments, the sustained-release polymer is chosen from apolyvinyl acetate-polyvinylpyrrolidone mixture and a poly(ethyleneoxide) polymer.

In certain embodiments, the sustained-release polymer is chosen fromKollidon® SR, POLYOX® N60K, and Carbopol®.

In certain embodiments, the sustained-release polymer is Kollidon® SR.

In certain embodiments, the sustained-release polymer is POLYOX® N60K.

In certain embodiments, the sustained-release polymer is Carbopol®.

In certain embodiments, the total weight is about 350 mg and about 700mg.

In certain embodiments, the extended-release pharmaceutical formulationcomprises from about 5 mg to about 30 mg of tetrabenazine ordihydrotetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 7.5 mg of tetrabenazine or dihydrotetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 12.5 mg of tetrabenazine or dihydrotetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 15 mg of tetrabenazine or dihydrotetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 25 mg tetrabenazine or dihydrotetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 30 mg of tetrabenazine or dihydrotetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 50 mg of tetrabenazine or dihydrotetrabenazine.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine with food, wherein the ratio of fed to fastedC_(max) of the total combined amount of dihydrotetrabenazine is greaterthan 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine for use in treatment of a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with food and theratio of fed to fasted C_(max) of the total combined amount ofdihydrotetrabenazine is greater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine for use in the manufacture of a medicament to treata VMAT2-mediated disease wherein the pharmaceutical composition isadministered with food and the ratio of fed to fasted C_(max) of thetotal combined amount of dihydrotetrabenazine is greater than 1.

In certain embodiments, the ratio of fed to fasted C_(max) is greaterthan about 1.4.

In certain embodiments, the ratio of fed to fasted C_(max) is greaterthan about 1.9.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine with food, wherein the ratio of fed to fastedAUC_(inf) of the total combined amount of dihydrotetrabenazine isgreater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine for use in treatment of a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with food and theratio of fed to fasted AUC_(inf) of the total combined amount ofdihydrotetrabenazine is greater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine for use in the manufacture of a medicament to treata VMAT2-mediated disease wherein the pharmaceutical composition isadministered with food and the ratio of fed to fasted AUC_(inf) of thetotal combined amount of dihydrotetrabenazine is greater than 1.

In certain embodiments, the ratio of fed to fasted AUC_(inf) is greaterthan about 1.1.

In certain embodiments, the ratio of fed to fasted AUC_(inf) is greaterthan about 1.2.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine with food, wherein the ratio of fed to fastedAUC_(t) of the total combined amount of dihydrotetrabenazine is greaterthan 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine for use in treatment of a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with food and theratio of fed to fasted AUC_(t) of the total combined amount ofdihydrotetrabenazine is greater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising tetrabenazine ordihydrotetrabenazine for use in the manufacture of a medicament to treata VMAT2-mediated disease wherein the pharmaceutical composition isadministered with food and the ratio of fed to fasted AUC_(t) of thetotal combined amount of dihydrotetrabenazine is greater than 1.

In certain embodiments, the ratio of fed to fasted AUC_(t) is greaterthan about 1.1.

In certain embodiments, the ratio of fed to fasted AUC_(t) is greaterthan about 1.2.

In certain embodiments, the VMAT2-mediated disorder is a chronichyperkinetic movement disorder.

In certain embodiments, the VMAT2-mediated disorder is selected from thegroup consisting of chronic hyperkinetic movement disorders,Huntington's disease, hemiballismus, chorea associated with Huntington'sdisease, senile chorea, tic disorders, tardive dyskinesia, dystonia,Tourette's syndrome, depression, cancer, rheumatoid arthritis,psychosis, multiple sclerosis, asthma, Parkinson's diseaselevodopa-induced dyskinesia, movement disorders, and oppositionaldefiant disorder.

In certain embodiments, the VMAT2-mediated disorder is Huntington'sdisease.

In certain embodiments, the VMAT2-mediated disorder is hemiballismus.

In certain embodiments, the VMAT2-mediated disorder is chorea associatedwith Huntington's disease.

In certain embodiments, the VMAT2-mediated disorder is senile chorea.

In certain embodiments, the VMAT2-mediated disorder is a tic disorder.

In certain embodiments, the VMAT2-mediated disorder is tardivedyskinesia.

In certain embodiments, the VMAT2-mediated disorder is dystonia.

In certain embodiments, the VMAT2-mediated disorder is Tourette'ssyndrome.

In certain embodiments, the VMAT2-mediated disorder is depression.

In certain embodiments, the VMAT2-mediated disorder is cancer.

In certain embodiments, the VMAT2-mediated disorder is rheumatoidarthritis.

In certain embodiments, the VMAT2-mediated disorder is psychosis.

In certain embodiments, the VMAT2-mediated disorder is multiplesclerosis.

In certain embodiments, the VMAT2-mediated disorder is asthma.

In certain embodiments, the VMAT2-mediated disorder is Parkinson'sdisease levodopa-induced dyskinesia.

In certain embodiments, the VMAT2-mediated disorder is levodopa-induceddyskinesia.

In certain embodiments, the VMAT2-mediated disorder is oppositionaldefiant disorder.

In certain embodiments of the present invention, compositions disclosedherein comprise the compound:

In certain embodiments of the present invention, compositions disclosedherein comprise the compound:

In certain embodiments of the present invention, compositions disclosedherein comprise one or more of the following compounds:

In certain embodiments of the present invention, compositions disclosedherein comprise one or more of the following compounds:

Certain compounds disclosed herein may possess useful VMAT2 inhibitingactivity, and may be used in the treatment or prophylaxis of a disorderin which VMAT2 plays an active role. Thus, certain embodiments alsoprovide pharmaceutical compositions comprising one or more compoundsdisclosed herein together with a pharmaceutically acceptable carrier, aswell as methods of making and using the compounds and compositions.Certain embodiments provide methods for inhibiting VMAT2. Otherembodiments provide methods for treating a VMAT2-mediated disorder in apatient in need of such treatment, comprising administering to saidpatient a therapeutically effective amount of a compound or compositionaccording to the present invention. Also provided is the use of certaincompounds disclosed herein for use in the manufacture of a medicamentfor the prevention or treatment of a disorder ameliorated by theinhibition of VMAT2.

The compounds as disclosed herein may also contain less prevalentisotopes for other elements, including, but not limited to, ¹³C or ¹⁴Cfor carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen, and ¹⁷O or¹⁸O for oxygen.

All publications and references cited herein are expressly incorporatedherein by reference in their entirety. However, with respect to anysimilar or identical terms found in both the incorporated publicationsor references and those explicitly put forth or defined in thisdocument, then those terms definitions or meanings explicitly put forthin this document shall control in all respects.

Tetrabenazine ((+/−)-cis-tetrabenazine, Nitoman®, Xenazine®, Tetmodis,Ro 1-9569), is a racemic mixture of(3R,11bR)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,and(3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor.Tetrabenazine is commonly prescribed for the treatment of choreaassociated with Huntington's disease (Savani et al., Neurology 2007,68(10), 797; and Kenney et al., Expert Review of Neurotherapeutics 2006,6(1), 7-17).

(3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

(3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

Tetrabenazine and its major metabolites alpha-dihydrotetrabenazine(α-HTBZ) and beta-dihydrotetrabenazine (β-HTBZ) are selective and potentinhibitors of the VMAT2. Scherman et al., Mol. Pharmacol. 1988,33(1):72-7. In humans, extensive hepatic metabolism of tetrabenazine toα-HTBZ and β-HTBZ by carbonyl reductase results in plasma concentrationsof tetrabenazine that are very low and are often below the limit ofdetection. Thus, α-HTBZ and β-HTBZ are thought to confer thepharmacological and therapeutic activity of orally administeredtetrabenazine in patients. In human plasma, α-HTBZ and β-HTBZ havehalf-lives of 7 hours and 5 hours, respectively (Xenazine® USPrescribing Information). Alpha(a)-HTBZ and β-HTBZ are each metabolizedinto pairs of mono-O-desmethyl metabolites (9-O-desmethyl-HTBZ and10-O-desmethyl-HTBZ) which are, in turn, conjugated by sulfonationand/or glucuronidation for excretion. The 9-O-desmethyl-β-HTBZmetabolite, which is derived from β-HTBZ, is also a major circulatingmetabolite. CYP2D6 is primarily responsible for 0-demethylation ofα-HTBZ and β-HTBZ in humans.

As used herein, the terms below have the meanings indicated.

The singular forms “a,” “an,” and “the” may refer to plural articlesunless specifically stated otherwise.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “n₁-n₂” is used, where n₁ and n₂ are the numbers, then unlessotherwise specified, this notation is intended to include the numbersthemselves and the range between them. This range may be integral orcontinuous between and including the end values.

The terms “tetrabenazine” and “(+/−)-cis-tetrabenazine” refer to aracemic mixture of(3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-oneand(3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,which have the following structures:

(3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

(3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

The term “(+/−)-trans-tetrabenazine” refers to a racemic mixture of(3R,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-oneand (3S,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,which have the following structures:

(3R,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

(3S,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as D-isomers and L-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disorder” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disease”,“syndrome”, and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder or one or more of the symptomsassociated with a disorder; or alleviating or eradicating the cause(s)of the disorder itself. As used herein, reference to “treatment” of adisorder is intended to include prevention. The terms “prevent,”“preventing,” and “prevention” refer to a method of delaying orprecluding the onset of a disorder; and/or its attendant symptoms,barring a subject from acquiring a disorder or reducing a subject's riskof acquiring a disorder.

The term “therapeutically effective amount” refers to the amount of acompound that, when administered, is sufficient to prevent developmentof, or alleviate to some extent, one or more of the symptoms of thedisorder being treated. The term “therapeutically effective amount” alsorefers to the amount of a compound that is sufficient to elicit thebiological or medical response of a cell, tissue, system, animal, orhuman that is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human, monkey, chimpanzee, gorilla, and the like),rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like),lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline,and the like. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman patient.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic disorder described in thepresent disclosure. Such administration encompasses co-administration ofthese therapeutic agents in a substantially simultaneous manner, such asin a single capsule having a fixed ratio of active ingredients or inmultiple, separate capsules for each active ingredient. In addition,such administration also encompasses use of each type of therapeuticagent in a sequential manner. In either case, the treatment regimen willprovide beneficial effects of the drug combination in treating thedisorders described herein.

The term “chronic hyperkinetic movement disorders” refers to disorderscharacterized by non-purposeful, repetitive, disordered motor acts,variously termed “compulsive”, “rhythmical”, or “stereotyped.” Inhumans, chronic hyperkinetic movement disorders can be psychogenic(e.g., tics), idiopathic (as in, e.g., Tourette's syndrome andParkinson's Disease, genetic (as in, e.g., the chorea characteristic ofHuntington's Disease), infectious (as in, e.g., Sydenham's Chorea), or,as in tardive dyskinesia, drug-induced. Unless otherwise stated,“chronic hyperkinetic movement disorders” refers to and includes allpsychogenic, idiopathic, genetic, and drug-induced movement disorders.

The term “stereotyped” refers to a repeated behavior that appearsrepetitively with slight variation or, less commonly, as a complexseries of movements.

The term “oppositional defiant disorder” or “ODD,” refers to apsychiatric disorder characterized by aggressiveness and a tendency topurposely bother and irritate others. According to diagnosticguidelines, oppositional defiant disorder is characterized by arepeating pattern of defiant, disobedient, hostile and negative behaviortoward authority figures. In one embodiment, oppositional defiantdisorder occurs for at least six months. In one embodiment, oppositionaldefiant disorder occurs more often than other children at the samedevelopmental level. In one embodiment, in order to be diagnosed withoppositional defiant disorder, children must exhibit four or more of thefollowing symptoms: (1) often loses temper, (2) often argues withadults, (3) often actively defies or refuses to comply with adults'requests or rules, (4) often blames others for his or her misbehavior ormistakes, (5) is often touchy or easily annoyed by others, (6) is oftenangry and resentful, or (7) is often spiteful and vindictive. In oneembodiment, behaviors that can be expected from a child withoppositional defiant disorder include: (1) arguing, (2) claiming not tocare about losing privileges as a consequence to negative behavior, (3)continually placing blame on others, (4) not accepting responsibilityfor actions, (5) ignoring directives, (6) playing adults against eachother (e.g. parent and teacher), (7) refusing to go to “time out,” (8)resistance to directions, (9) stubbornness, (10) testing limits, and(11) unwillingness to compromise, give in, or negotiate with adults orpeers.

The term “Parkinson's disease levodopa-induced dyskinesia,”“levodopa-induced dyskinesia,” or “LID” refers to an abnormal muscularactivity disorder characterized by either disordered or excessivemovement (referred to as “hyperkinesia” or “dyskinesia”), or slowness,or a lack of movement (referred to as “hypokinesia,” “bradykinesia,” or“akinesia”). Based on their relationship with levodopa dosing,levodopa-induced dyskinesias are classified as peak-dose, diphasic, offstate, on state, and yo yo dyskinesias. Peak-dose dyskinesias are themost common forms of LID and are related to peak plasma (and possiblyhigh striatal) levels of levodopa. They involve the head, trunk, andlimbs, and sometimes respiratory muscles. Dose reduction can amelioratethem, frequently at the cost of deterioration of parkinsonism. Peak-dosedyskinesias are usually choreiform, though in the later stages dystoniacan superimpose. Diphasic dyskinesias develop when plasma levodopalevels are rising or falling, but not with the peak levels. They arealso called D-I-D (dyskinesia-improvement-dyskinesia). D-I-D arecommonly dystonic in nature, though chorea or mixed pattern may occur.They do not respond to levodopa dose reduction and may rather improvewith high dose of levodopa. “Off” state dystonias occur when plasmalevodopa levels are low (for example, in the morning). They are usuallypure dystonia occurring as painful spasms in one foot. They respond tolevodopa therapy. Rare forms of LID include “on” state dystonias(occurring during higher levels of levodopa) and yo-yo dyskinesia(completely unpredictable pattern).

The term “VMAT2” refers to vesicular monoamine transporter 2, anintegral membrane protein that acts to transport monoamines—particularlyneurotransmitters such as dopamine, norepinephrine, serotonin, andhistamine—from cellular cytosol into synaptic vesicles.

The term “VMAT2-mediated disorder,” refers to a disorder that ischaracterized by abnormal VMAT2 activity. A VMAT2-mediated disorder maybe completely or partially mediated by modulating VMAT2. In particular,a VMAT2-mediated disorder is one in which inhibition of VMAT2 results insome effect on the underlying disorder e.g., administration of a VMAT2inhibitor results in some improvement in at least some of the patientsbeing treated.

The term “VMAT2 inhibitor”, “inhibit VMAT2”, or “inhibition of VMAT2”refers to the ability of a compound disclosed herein to alter thefunction of VMAT2. A VMAT2 inhibitor may block or reduce the activity ofVMAT2 by forming a reversible or irreversible covalent bond between theinhibitor and VMAT2 or through formation of a noncovalently boundcomplex. Such inhibition may be manifest only in particular cell typesor may be contingent on a particular biological event. The term “VMAT2inhibitor”, “inhibit VMAT2”, or “inhibition of VMAT2” also refers toaltering the function of VMAT2 by decreasing the probability that acomplex forms between a VMAT2 and a natural substrate.

The term “deuterated analog of” refers to a compound having an identicalchemical structure as a given non-isotopically enriched, wherein one ormore hydrogen-containing positions on the non-isotopically enrichedmolecule are enriched with deuterium above the naturally occurringlevel.

The term “deuterated analog of pirfenidone” can be defined by referenceto the general structural formulas and specific compounds of U.S. Pat.No. 8,383,823, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of phenylephrine” can be defined byreference to the general structural formulas and specific compounds ofU.S. Pat. No. 7,745,665, which is hereby incorporated by reference inits entirety.

The term “deuterated analog of ethambutol” can be defined by referenceto the general structural formulas and specific compounds of U.S. Pat.No. 7,767,860, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of venlafaxine” can be defined by referenceto the general structural formulas and specific compounds of U.S. Pat.No. 7,456,317, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of zolipidem” can be defined by reference tothe general structural formulas and specific compounds of U.S. Pat. No.7,772,248, which is hereby incorporated by reference in its entirety.

The terms “deuterated analog of esomeprazole, lansoprazole, omeprazole,pantoprazole, or rabeprazole” can be defined by reference to the generalstructural formulas and specific compounds of U.S. Pat. No. 7,598,273,which is hereby incorporated by reference in its entirety.

The term “deuterated analog of sitaxentan” can be defined by referenceto the general structural formulas and specific compounds of U.S. Pat.No. 7,863,308, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of codeine, hydrocodone, morphine, oroxycodone” can be defined by reference to the general structuralformulas and specific compounds of U.S. Pat. No. 7,872,013, which ishereby incorporated by reference in its entirety.

The term “deuterated analog of almotriptan, eletriptan, naratriptan,sumatriptan, or zolmitriptan” can be defined by reference to the generalstructural formulas and specific compounds of U.S. Patent PublicationNo. 20080103189, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of ketamine” can be defined by reference tothe general structural formulas and specific compounds of U.S. Pat. No.7,638,651, which is hereby incorporated by reference in its entirety.

The term “deuterated analog of ranolazine” can be defined by referenceto the general structural formulas and specific compounds of U.S. PatentPublication No. 20080312247, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of desmethylvenlafaxine” can be defined byreference to the general structural formulas and specific compounds ofU.S. Patent Publication No. 20080234257, which is hereby incorporated byreference in its entirety.

The term “deuterated analog of mirabegron” can be defined by referenceto the general structural formulas and specific compounds of U.S. Pat.No. 8,586,760, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of ticagrelor” can be defined by referenceto the general structural formulas and specific compounds of U.S. PatentPublication No. 20120301458, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of darapladib” can be defined by referenceto the general structural formulas and specific compounds of U.S. PatentPublication No. 20110306552, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of rilapladib” can be defined by referenceto the general structural formulas and specific compounds of U.S. Pat.No. 8,575,348, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of nilotinib” can be defined by reference tothe general structural formulas and specific compounds of U.S. PatentPublication No. 20110053968, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of tofacitinib” can be defined by referenceto the general structural formulas and specific compounds of U.S. Pat.No. 8,299,084, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of apixaban” can be defined by reference tothe general structural formulas and specific compounds of U.S. PatentPublication No. 20100130543, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of lumiracoxib” can be defined by referenceto the general structural formulas and specific compounds of U.S. Pat.No. 8,227,451, which is hereby incorporated by reference in itsentirety.

The term “deuterated analog of solabegron” can be defined by referenceto the general structural formulas and specific compounds of U.S. PatentPublication No. 20100120861, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of riociguat” can be defined by reference tothe general structural formulas and specific compounds of U.S. PatentPublication No. 20110201626, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of cariprazine” can be defined by referenceto the general structural formulas and specific compounds of U.S. PatentPublication No. 20110117214, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of neratinib or pelitinib” can be defined byreference to the general structural formulas and specific compounds ofPCT Publication No. WO 2011123524, which is hereby incorporated byreference in its entirety.

The term “deuterated analog of fostamatinib or R-406” can be defined byreference to the general structural formulas and specific compounds ofU.S. Patent Publication No. 20110206661, which is hereby incorporated byreference in its entirety.

The term “deuterated analog of dihydrotetrabenazine” can be defined byreference to the general structural formulas and specific compounds ofU.S. Patent Publication No. 20120003330, which is hereby incorporated byreference in its entirety.

The term “deuterated analog of L-838417” can be defined by reference tothe general structural formulas and specific compounds of PCTPublication Nos. WO2010025407, WO2013170242, and WO2013170243, each ofwhich are hereby incorporated by reference in its entirety.

The term “deuterated analog of pentoxifylline or pentoxifyllinemetabolites” can be defined by reference to the general structuralformulas and specific compounds of PCT Publication Nos. WO 2009108375,WO 2009108383, WO 2012031073, WO 2012031072, and WO 2013159006, each ofwhich are hereby incorporated by reference in their entireties.

The term “deuterated analog of levodopa” can be defined by reference tothe general structural formulas and specific compounds of PCTPublication No. WO 2007093450, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of carbidopa” refers to an analog ofcarbidopa wherein one or more hydrogen-containing positions on thenon-isotopically enriched molecule are enriched with deuterium above thenaturally occurring level.

Non-isotopically enriched carbidopa is described in Falck, Drug Intel.Clin. Pharm., 1976, 10(2), 84-5; Pinder et al., Drugs, 1976, 11(5),329-77; and Rao et al., Adv. Neurol., 1973, 3, 73-7; each of which arehereby incorporated by reference in their entireties.

The term “deuterated analog of amantidine” refers to an analog ofamantidine wherein one or more hydrogen-containing positions on thenon-isotopically enriched molecule are enriched with deuterium above thenaturally occurring level.

Non-isotopically enriched amantidine is described in Danielczyk, J.Neural. Trans., Suppl., 1995, 46(Parkinsons Disease: Experimental Modelsand Therapy), 399-405; Ebadi et al., Parkinson's Disease, 2005, 685-690;Singer et al., J. Appl. Res. (2006), 6(3), 240-245; Dashtipour et al.,Neurol. Disease Ther., 2007, 92(Handbook of Parkinson's Disease (4thEdition)), 293-307, each of which are hereby incorporated by referencein their entireties.

The term “deuterated analog of nintedanib” refers to an analog ofnintedanib wherein one or more hydrogen-containing positions on thenon-isotopically enriched molecule are enriched with deuterium above thenaturally occurring level.

Non-isotopically enriched nintedanib is described in Roth et al., J.Med. Chem., 2009, 52(14), 4466-4480; WO 2004017948; WO 2006067165; andU.S. Pat. No. 6,762,180, each of which are hereby incorporated byreference in their entireties.

The term “deuterated analog of pridopidine” can be defined by referenceto the general structural formulas and specific compounds of PCTPublication No. WO 2012028635, which is hereby incorporated by referencein its entirety.

The term “deuterated analog of dipraglurant” refers to an analog ofdipraglurant wherein one or more hydrogen-containing positions on thenon-isotopically enriched molecule are enriched with deuterium above thenaturally occurring level.

Non-isotopically enriched dipraglurant is described as compound ofExample 74 of PCT Publication Nos. WO 2005123703, and further describedin WO 2013186311, each of which are hereby incorporated by reference intheir entireties.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without excessivetoxicity, irritation, allergic response, immunogenecity, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. Each component must be “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation. It must also be suitable for use in contact with the tissueor organ of humans and animals without excessive toxicity, irritation,allergic response, immunogenecity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition; Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition; Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004).

The terms “active ingredient,” “active compound,” and “active substance”refer to a compound, which is administered, alone or in combination withone or more pharmaceutically acceptable excipients or carriers, to asubject for treating, preventing, or ameliorating one or more symptomsof a disorder.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a disorder.

The terms “extended release,” “extended release formulation,” “sustainedrelease,” and “sustained release formulation,” refers to a dosage formcontaining a release controlling excipient, wherein the duration orplace of release of the active substance from a dosage form is delayedwhen compared with a conventional immediate release dosage form. Incertain embodiments an extended release dosage form results in an activesubstance plasma concentration that is characterized by a slower rate ofrise (delayed T_(max)) or a lower peak concentration (lowerdose-normalized C_(max)). In certain embodiments an extended releasedosage form results in similar or greater systemic exposure (AUC) as aconventional immediate release dosage form having an equivalent amountof active substance.

The term “release controlling excipient” refers to an excipient whoseprimary function is to modify the duration or place of release of theactive substance from a dosage form as compared with a conventionalimmediate release dosage form.

The term “nonrelease controlling excipient” refers to an excipient whoseprimary function do not include modifying the duration or place ofrelease of the active substance from a dosage form as compared with aconventional immediate release dosage form.

The term “prodrug” refers to a compound functional derivative of thecompound as disclosed herein and is readily convertible into the parentcompound in vivo. Prodrugs are often useful because, in some situations,they may be easier to administer than the parent compound. They may, forinstance, be bioavailable by oral administration whereas the parentcompound is not. The prodrug may also have enhanced solubility inpharmaceutical compositions over the parent compound. A prodrug may beconverted into the parent drug by various mechanisms, includingenzymatic processes and metabolic hydrolysis. See Harper, Progress inDrug Research 1962, 4, 221-294; Morozowich et al. in “Design ofBiopharmaceutical Properties through Prodrugs and Analogs,” Roche Ed.,APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drug in DrugDesign, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987;“Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al., Curr.Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. DeliveryRev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365;Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asgharnejad in“Transport Processes in Pharmaceutical Systems,” Amidon et al., Ed.,Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab.Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug DeliveryRev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12;Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled DrugDelivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8,1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130;Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al.,J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem.Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4,49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977,409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu andThakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151;Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino andBorchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv.Drug Delivery Rev. 1999, 39, 63-80; Waller et al., Br. J. Clin. Pharmac.1989, 28, 497-507.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The term “therapeutically acceptable salt,” as used herein,represents salts or zwitterionic forms of the compounds disclosed hereinwhich are therapeutically acceptable as defined herein. The salts can beprepared during the final isolation and purification of the compounds orseparately by reacting the appropriate compound with a suitable acid orbase. Therapeutically acceptable salts include acid and basic additionsalts. For a more complete discussion of the preparation and selectionof salts, refer to “Handbook of Pharmaceutical Salts, Properties, andUse,” Stah and Wermuth, Ed. (Wiley-VCH and VHCA, Zurich, 2002) and Bergeet al., J. Pharm. Sci. 1977, 66, 1-19.

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

References to a compound of a formula and subgroups thereof includeionic forms, polymorphs, pseudopolymorphs, amorphous forms, and solvatesthereof “Crystalline form,” “polymorph,” and “novel form” may be usedinterchangeably herein, and are meant to include all crystalline andamorphous forms of the compound, including, for example, polymorphs,pseudopolymorphs, solvates (including hydrates), co crystals, unsolvatedpolymorphs (including anhydrates), conformational polymorphs, andamorphous forms, as well as mixtures thereof, unless a particularcrystalline or amorphous form is referred to. In some embodiments,references to a compound include polymorphs, solvates, and/or cocrystals thereof. In some embodiments, references to a compound of aformula and subgroups thereof include polymorphs thereof. Similarly, theterm “salts” includes polymorphs of salts of compounds.

Pharmaceutical Formulations

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical composition. Accordingly, provided herein arepharmaceutical compositions which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, prodrugs, or solvates thereof, together with one or morepharmaceutically acceptable carriers thereof and optionally one or moreother therapeutic ingredients. Proper formulation is dependent upon theroute of administration chosen. Any of the well-known techniques,carriers, and excipients may be used as suitable and as understood inthe art; e.g., in Remington's Pharmaceutical Sciences. Thepharmaceutical compositions disclosed herein may be manufactured in anymanner known in the art, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or compression processes. The pharmaceuticalcompositions may also be formulated as a modified release dosage form,including delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art (see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugsand the Pharmaceutical Science, Marcel Dekker, Inc., New York, N.Y.,2002; Vol. 126).

The compositions include those suitable for oral administration. Thecompositions may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy.Typically, these methods include the step of bringing into association acompound of the subject invention or a pharmaceutically salt, prodrug,or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In certain embodiments, diluents are selected from the group consistingof mannitol powder, spray dried mannitol, microcrystalline cellulose,lactose, dicalcium phosphate, tricalcium phosphate, starch,pregelatinized starch, compressible sugars, silicified microcrystallinecellulose, and calcium carbonate.

In certain embodiments, surfactants are selected from the groupconsisting of Tween 80, sodium lauryl sulfate, and docusate sodium.

In certain embodiments, binders are selected from the group consistingof povidone (PVP) K29/32, hydroxypropylcellulose (HPC),hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), corn starch,pregelatinized starch, gelatin, and sugar.

In certain embodiments, lubricants are selected from the groupconsisting of magnesium stearate, stearic acid, sodium stearyl fumarate,calcium stearate, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, polyethylene glycol 4000-6000, talc, and glyceryl behenate.

In certain embodiments, sustained release polymers are selected from thegroup consisting of POLYOX® (poly (ethylene oxide), POLYOX® N60K grade,Kollidon® SR, HPMC, HPMC (high viscosity), HPC, HPC (high viscosity),and Carbopol®.

In certain embodiments, extended/controlled release coating are selectedfrom a group of ethylcellulose polymers, such as ETHOCEL™ and Surelease®Aqueous Ethylcellulose Dispersions.

In certain embodiments, antioxidants are selected from a groupconsisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), sodium ascorbate, and α-tocopherol.

In certain embodiments, tablet coatings are selected from the group ofOpadry® 200, Opadry® II, Opadry® fx, Opadry® amb, Opaglos® 2, Opadry®tm, Opadry®, Opadry® NS, Opalux®, Opatint®, Opaspray®, Nutraficient®.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

Compounds may be administered orally at a dose of from 0.1 to 500 mg/kgper day. The dose range for adult humans is generally from 5 mg to 2g/day. Tablets or other forms of presentation provided in discrete unitsmay conveniently contain an amount of one or more compounds which iseffective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The precise amount of compound administered to a patient will be theresponsibility of the attendant physician. The specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diets, time of administration, route ofadministration, rate of excretion, drug combination, the precisedisorder being treated, and the severity of the disorder being treated.Also, the route of administration may vary depending on the disorder andits severity.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisorder.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be given continuouslyor temporarily suspended for a certain length of time (i.e., a “drugholiday”).

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disorder is retained.Patients can, however, require intermittent treatment on a long-termbasis upon any recurrence of symptoms.

Indications

Disclosed herein are methods of treating a VMAT2-mediated disordercomprising administering to a subject having or suspected of having sucha disorder, a therapeutically effective amount of a compound orcomposition as disclosed herein or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

VMAT2-mediated disorders, include, but are not limited to, chronichyperkinetic movement disorders, Huntington's disease, hemiballismus,chorea associated with Huntington's disease, senile chorea, ticdisorders, tardive dyskinesia, dystonia, Tourette's syndrome,depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis,asthma, Parkinson's disease levodopa-induced dyskinesia, movementdisorders, and oppositional defiant disorder, and/or any disorder whichcan lessened, alleviated, or prevented by administering a VMAT2inhibitor.

Movement disorders include, but are not limited to, ataxia, corticobasaldegeneration, dyskinesias (paroxysmal), dystonia (general, segmental,focal) including blepharospasm, spasmodic torticollis (cervicaldystonia), writer's cramp (limb dystonia), laryngeal dystonia (spasmodicdysphonia), and oromandibular dystonia, essential tremor, hereditaryspastic paraplegia, Huntington's Disease, multiple system atrophy (ShyDrager Syndrome), myoclonus, Parkinson's Disease, progressivesupranuclear palsy, restless legs syndrome, Rett Syndrome, spasticitydue to stroke, cerebral palsy, multiple sclerosis, spinal cord or braininjury, Sydenham's Chorea, tardive dyskinesia/dystonia, tics, Tourette'sSyndrome, and Wilson's Disease.

Plasma levels of the compound as disclosed herein, or metabolitesthereof, may be measured using the methods described by Li et al. RapidCommunications in Mass Spectrometry 2005, 19, 1943-1950; Jindal, et al.,Journal of Chromatography, Biomedical Applications 1989, 493(2), 392-7;Schwartz, et al., Biochemical Pharmacology 1966, 15(5), 645-55; Mehvar,et al., Drug Metabolism and Disposition 1987, 15(2), 250-5; Roberts etal., Journal of Chromatography, Biomedical Applications 1981, 226(1),175-82; and any references cited therein or any modifications madethereof.

Examples of cytochrome P₄₅₀ isoforms in a mammalian subject include, butare not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6,CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2,CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11,CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1,CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2,CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39,CYP46, and CYP51.

Examples of monoamine oxidase isoforms in a mammalian subject include,but are not limited to, MAO_(A), and MAO_(B).

The inhibition of the cytochrome P₄₅₀ isoform is measured by the methodof Ko et al. (British Journal of Clinical Pharmacology, 2000, 49,343-351). The inhibition of the MAO_(A) isoform is measured by themethod of Weyler et al. (J. Biol Chem. 1985, 260, 13199-13207). Theinhibition of the MAO_(B) isoform is measured by the method of Uebelhacket al. (Pharmacopsychiatry, 1998, 31, 187-192).

Examples of polymorphically-expressed cytochrome P₄₅₀ isoforms in amammalian subject include, but are not limited to, CYP2C8, CYP2C9,CYP2C19, and CYP2D6.

The metabolic activities of liver microsomes, cytochrome P450 isoforms,and monoamine oxidase isoforms are measured by the methods describedherein.

Examples of improved disorder-control and/or disorder-eradicationendpoints, or improved clinical effects include, but are not limited to,change from baseline in the chorea score of the Unified Huntington'sDisease Rating Scale (UHDRS).

Examples of improved disorder-control and/or disorder-eradicationendpoints, or improved clinical effects include, but are not limited to:

-   -   a. improved Unified Parkinson's Disease Rating Scale scores;    -   b. improved Abnormal Involuntary Movement Scale scores;    -   c. improved Goetz Dyskinesia Rating Scale scores;    -   d. improved Unified Dyskinesia Rating Scale scores;    -   e. improved PDQ-39 Parkinson's Disease Questionnaire scores; and    -   f. improved Global Primate Dyskinesia Rating Scale scores.

Examples of improved disorder-control and/or disorder-eradicationendpoints, or improved clinical effects in the treatment of oppositionaldefiant disorder include, but are not limited to:

-   -   a. reduced aggressiveness;    -   b. reduction of the rate or severity of incidents of temper        loss;    -   c. reduction of the rate or severity of incidents of arguing        with adults;    -   d. reduction of the rate or severity of incidents of defiance or        refusal to comply with adults' requests or rules;    -   e. reduction of the rate or severity of incidents of blaming        others for his or her misbehavior or mistakes;    -   f reduced touchiness or ease of annoyance by others;    -   g. reduced anger and/or resentfulness;    -   h. reduced spitefulness and/or vindictiveness;    -   i. reduction of the rate or severity of incidents of arguing;    -   j. reduction of the rate or severity of incidents of claiming        not to care about losing privileges as a consequence to negative        behavior;    -   k. reduction of the rate or severity of incidents of placing        blame on others;    -   l. reduction of the rate or severity of incidents of not        accepting responsibility for actions;    -   m. reduction of the rate or severity of incidents of ignoring        directives;    -   n. reduction of the rate or severity of incidents of playing        adults against each other;    -   o. reduction of the rate or severity of incidents of refusing to        go to “time out”;    -   p. reduction of the rate or severity of incidents of resisting        directions;    -   q. reduced stubbornness;    -   r. reduction of the rate or severity of incidents of testing        limits; and    -   s. reduction of the rate or severity of incidents of        unwillingness to compromise, give in, or negotiate with adults        or peers.

Examples of diagnostic hepatobiliary function endpoints include, but arenot limited to, alanine aminotransferase (“ALT”), serum glutamic-pyruvictransaminase (“SGPT”), aspartate aminotransferase (“AST” or “SGOT”),ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonialevels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” or“GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liverultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein.Hepatobiliary endpoints are compared to the stated normal levels asgiven in “Diagnostic and Laboratory Test Reference”, 4^(th) edition,Mosby, 1999. These assays are run by accredited laboratories accordingto standard protocol.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

Combination Therapy

The compounds disclosed herein may also be combined or used incombination with other agents useful in the treatment of VMAT2-mediateddisorders. Or, by way of example only, the therapeutic effectiveness ofone of the compounds described herein may be enhanced by administrationof an adjuvant (i.e., by itself the adjuvant may only have minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the patient is enhanced).

Such other agents, adjuvants, or drugs, may be administered, by a routeand in an amount commonly used therefor, simultaneously or sequentiallywith a compound as disclosed herein. When a compound as disclosed hereinis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compounddisclosed herein may be utilized, but is not required.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more dopamine precursors, including, but not limited to,levodopa.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more DOPA decarboxylase inhibitors, including, but notlimited to, carbidopa.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more catechol-O-methyl transferase (COMT) inhibitors,including, but not limited to, entacapone and tolcapone.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more dopamine receptor agonists, including, but not limitedto, apomorphine, bromocriptine, ropinirole, and pramipexole.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more neuroprotective agents, including, but not limited to,selegeline and riluzole.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more NMDA antagonists, including, but not limited to,amantidine.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more anti-psychotics, including, but not limited to,chlorpromazine, levomepromazine, promazine, acepromazine,triflupromazine, cyamemazine, chlorproethazine, dixyrazine,fluphenazine, perphenazine, prochlorperazine, thiopropazate,trifluoperazine, acetophenazine, thioproperazine, butaperazine,perazine, periciazine, thioridazine, mesoridazine, pipotiazine,haloperidol, trifluperidol, melperone, moperone, pipamperone,bromperidol, benperidol, droperidol, fluanisone, oxypertine, molindone,sertindole, ziprasidone, flupentixol, clopenthixol, chlorprothixene,thiothixene, zuclopenthixol, fluspirilene, pimozide, penfluridol,loxapine, clozapine, olanzapine, quetiapine, tetrabenazine, sulpiride,sultopride, tiapride, remoxipride, amisulpride, veralipride,levosulpiride, lithium, prothipendyl, risperidone, clotiapine,mosapramine, zotepine, pripiprazole, and paliperidone.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more benzodiazepines (“minor tranquilizers”), including, butnot limited to alprazolam, adinazolam, bromazepam, camazepam, clobazam,clonazepam, clotiazepam, cloxazolam, diazepam, ethyl loflazepate,estizolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam,medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassiumclorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam, andchlordiazepoxide.

In certain embodiments, the compounds disclosed herein can be combinedwith olanzapine or pimozide.

The compounds disclosed herein can also be administered in combinationwith other classes of compounds, including, but not limited to,anti-retroviral agents; CYP3A inhibitors; CYP3A inducers; proteaseinhibitors; adrenergic agonists; anti-cholinergics; mast cellstabilizers; xanthines; leukotriene antagonists; glucocorticoidstreatments; local or general anesthetics; non-steroidalanti-inflammatory agents (NSAIDs), such as naproxen; antibacterialagents, such as amoxicillin; cholesteryl ester transfer protein (CETP)inhibitors, such as anacetrapib; anti-fungal agents, such asisoconazole; sepsis treatments, such as drotrecogin-α; steroidals, suchas hydrocortisone; local or general anesthetics, such as ketamine;norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopaminereuptake inhibitors (DARIs), such as methylphenidate;serotonin-norepinephrine reuptake inhibitors (SNRIs), such asmilnacipran; sedatives, such as diazepham; norepinephrine-dopaminereuptake inhibitor (NDRIs), such as bupropion;serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such asvenlafaxine; monoamine oxidase inhibitors, such as selegiline;hypothalamic phospholipids; endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; opioids, such as tramadol;thromboxane receptor antagonists, such as ifetroban; potassium channelopeners; thrombin inhibitors, such as hirudin; hypothalamicphospholipids; growth factor inhibitors, such as modulators of PDGFactivity; platelet activating factor (PAF) antagonists; anti-plateletagents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, andtirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine andCS-747), and aspirin; anticoagulants, such as warfarin; low molecularweight heparins, such as enoxaparin; Factor VIIa Inhibitors and FactorXa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors;vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilatand gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin,lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin,nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin,or atavastatin or visastatin); squalene synthetase inhibitors; fibrates;bile acid sequestrants, such as questran; niacin; anti-atheroscleroticagents, such as ACAT inhibitors; MTP Inhibitors; calcium channelblockers, such as amlodipine besylate; potassium channel activators;alpha-muscarinic agents; beta-muscarinic agents, such as carvedilol andmetoprolol; antiarrhythmic agents; diuretics, such as chlorothlazide,hydrochiorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichioromethiazide,polythiazide, benzothlazide, ethacrynic acid, tricrynafen,chlorthalidone, furosenilde, musolimine, bumetanide, triamterene,amiloride, and spironolactone; thrombolytic agents, such as tissueplasminogen activator (tPA), recombinant tPA, streptokinase, urokinase,prourokinase, and anisoylated plasminogen streptokinase activatorcomplex (APSAC); anti-diabetic agents, such as biguanides (e.g.metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g. troglitazone,rosiglitazone and pioglitazone), and PPAR-gamma agonists;mineralocorticoid receptor antagonists, such as spironolactone andeplerenone; growth hormone secretagogues; aP2 inhibitors;phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil,vardenafil); protein tyrosine kinase inhibitors; antiinflammatories;antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf),mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;anticancer agents and cytotoxic agents (e.g., alkylating agents, such asnitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, andtriazenes); antimetabolites, such as folate antagonists, purineanalogues, and pyrridine analogues; antibiotics, such as anthracyclines,bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such asL-asparaginase; farnesyl-protein transferase inhibitors; hormonalagents, such as glucocorticoids (e.g., cortisone),estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone antagonists, and octreotideacetate; microtubule-disruptor agents, such as ecteinascidins;microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;prenyl-protein transferase inhibitors; and cyclosporins; steroids, suchas prednisone and dexamethasone; cytotoxic drugs, such as azathiprineand cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNFantibodies or soluble TNF receptor, such as etanercept, rapamycin, andleflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxiband rofecoxib; and miscellaneous agents such as, hydroxyurea,procarbazine, mitotane, hexamethylmelamine, gold compounds, platinumcoordination complexes, such as cisplatin, satraplatin, and carboplatin.

Thus, in another aspect, certain embodiments provide methods fortreating VMAT2-mediated disorders in a subject in need of such treatmentcomprising administering to said subject an amount of a compounddisclosed herein effective to reduce or prevent said disorder in thesubject, in combination with at least one additional agent for thetreatment of said disorder. In a related aspect, certain embodimentsprovide therapeutic compositions comprising at least one compounddisclosed herein in combination with one or more additional agents forthe treatment of VMAT2-mediated disorders.

General Synthetic Methods for Preparing Compounds

The compounds as disclosed herein can be prepared by methods known toone of skill in the art and routine modifications thereof, and/orfollowing procedures similar to those described in US 20100130480(paragraphs [0093]-[0121]), US 20120003330 (paragraphs [0104]-[0162]),WO 2005077946; WO 2008/058261; EP 1716145; Lee et al., J. Med. Chem.,1996, (39), 191-196; Kilbourn et al., Chirality, 1997, (9), 59-62; Boldtet al., Synth. Commun., 2009, (39), 3574-3585; Rishel et al., J. Org.Chem., 2009, (74), 4001-4004; DaSilva et al., Appl. Radiat. Isot., 1993,44(4), 673-676; Popp et al., J. Pharm. Sci., 1978, 67(6), 871-873;Ivanov et al., Heterocycles 2001, 55(8), 1569-1572; U.S. Pat. Nos.2,830,993; 3,045,021; WO 2007130365; WO 2008058261; U.S. Pat. Nos.7,638,651; 8,383,823; 7,745,665; 7,767,860; 7,456,317; 7,772,248;7,598,273; 7,863,308; 7,872,013; US 20080103189; U.S. Pat. No.7,638,651; US 20080312247; US 20080234257; U.S. Pat. No. 8,586,760; US20120301458; US 20110306552; U.S. Pat. No. 8,575,348; US 20110053968;U.S. Pat. No. 8,299,084; US 20100130543; U.S. Pat. No. 8,227,451; US20100120861; US 20110201626; US 20110117214; WO 2011123524; US20110206661; US 20120003330; WO2010025407; WO2013170242; WO2013170243;WO 2009108375; WO 2009108383; WO 2012031073; WO 2012031072; and WO2013159006, which are hereby incorporated in their entirety, andreferences cited therein and routine modifications thereof.

The invention is further illustrated by the following examples.

FORMULATION EXAMPLES

Examples 1-5, and other Examples described herein, may be made by themethods disclosed in FIG. 1.

Example 1 25 mg Tetrabenazine Gastro-Erosional Extended Release (SmallTablet) (Formulation A)

Table 1 below discloses the elements of a 350 mg total weightgastro-erosional granulation formulation tablet comprising 25 mg (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.

TABLE 1 Material mg/tab % Tetrabenazine (milled) 25 7.1 Mannitol Powder177.9 50.8 Microcrystalline Cellulose 59.3 16.9 PVP K29/32 14 4.0 Tween80 (Polysorbate 80) 3.8 1.1 Mannogem ® EZ (spray dried mannitol) 31.59.0 POLYOX ® N60K 35 10.0 Magnesium Stearate 3.5 1.0 Totals: 350.0 100.0

Tetrabenazine (milled) is combined along with Mannitol Powder,Microcrystalline Cellulose, PVP K29/32 and Tween 80 (Polysorbate 80)into a high shear granulator and initially dry mixed at high impellerand chopper speed for 5 minutes. While mixing at high impeller speed andlow chopper speed, Purified Water is added to the mixing powders togranulate the material. Additional mixing and water addition with highimpeller and high chopper speed continues until the desired granulationend-point is achieved. The resulting granulation is wet screened tobreak up any oversized agglomerates and the material is added to a fluidbed drier and dried at 60° C. until the desired L.O.D. (loss on drying)is achieved. The dried material is sieved through a #20 mesh screen andthe oversized material is milled to a particle size of just under 20mesh in size. The dried and sized material is combined with Spray DriedMannitol and POLYOX® N60K into a diffusive mixer (V-Blender) where it isblended for 15 minutes. Magnesium Stearate is then passed through a #30mesh screen and added to the blended material in the V-Blender. Thecontents are then lubricated for 3 minutes and discharged for tabletcompression. Using a rotary tablet press fitted with punches and dies ofthe desired shape and size, the lubricated blend is compressed intotablets of a theoretical weight of 350 mg.

Example 2 15 mg Tetrabenazine Gastro-Erosional Extended Release (SmallTablet) (Formulation A)

Table 2 below discloses the elements of a 350 mg total weightgastro-erosional granulation formulation tablet comprising 15 mgtetrabenazine.

TABLE 2 Material mg/tab % Tetrabenazine (milled) 15.0 4.3 MannitolPowder 185.4 53.0 Microcrystalline Cellulose 61.8 17.7 PVP K29/32 14.04.0 Tween 80 (Polysorbate 80) 3.8 1.1 Mannogem EZ (spray dried mannitol)31.5 9.0 POLYOX ® N60K 35.0 10.0 Magnesium Stearate 3.5 1.0 Totals:350.0 100.0

Same process as described for Example 1.

Example 3 15 mg Tetrabenazine Gastro-Retentive Extended Release (LargeTablet) (Formulation B)

Table 3 below discloses the elements of a 700 mg total weightgastro-retentive formulation tablet comprising 15 mg tetrabenazine. Thegastro-retentive tablet is an elongated capsule having dimensions ofapproximately 0.7087 in. long by 0.3071 in. wide, having rounded endswith a cup depth of 0.0540 in. on each opposing side, as shown in FIG.2.

TABLE 3 Material mg/tab % Tetrabenazine (milled) 15.0 2.1 MannitolPowder 357.5 51.1 Microcrystalline Cellulose 119.0 17.0 PVP K29/32 26.03.7 Tween 80 (Polysorbate 80) 7.5 1.1 Mannogem EZ (spray dried mannitol)28.0 4.0 POLYOX ® N60K 140.0 20.0 Magnesium Stearate 7.0 1.0 Totals:700.0 100.0

Same Process as described for Example 1. But theoretical compressionweight is 700 mg.

Example 4 15 mg Tetrabenazine Gastro-Retentive Extended Release (LargeTablet) (Formulation B)

Table 4 below discloses the elements of a 700 mg total weightgastro-retentive formulation tablet comprising 15 mg tetrabenazine. Thegastro-retentive tablet is an elongated capsule having dimensions ofapproximately 0.7087 in. long by 0.3071 in. wide, having rounded endswith a cup depth of 0.0540 in. on each opposing side, as shown in FIG.2.

TABLE 4 Material mg/tab % Tetrabenazine (milled) 15.0 2.1 MannitolPowder 357.5 51.1 Microcrystalline Cellulose 119.0 17.0 PVP K29/32 26.03.7 Tween 80 (Polysorbate 80) 7.5 1.1 Mannogem ® EZ (spray driedmannitol) 45.5 6.5 POLYOX ® N60K 122.5 17.5 Magnesium Stearate 7.0 1.0Totals: 700.0 100.0

Same Process as described for Example 1. But theoretical compressionweight is 700 mg.

Example 5 6 mg Tetrabenazine Immediate Release Tablet

Table 5 below discloses the elements of a 125 mg total weightimmediate-release tablet comprising 6 mg tetrabenazine.

TABLE 5 Material mg/tab % Tetrabenazine (milled) 6.0 4.8 Mannitol Powder75.0 60.0 Microcrystalline Cellulose 25.0 20.0 Sodium Starch Glycolate2.5 2.0 PVP K29/32 6.0 4.8 Tween 80 (Polysorbate 80) 1.0 0.8 Mannogem ®EZ (spray dried mannitol) 5.8 4.6 Sodium Starch Glycolate 2.5 2.0Magnesium Stearate 1.2 1.0 Totals: 125.0 100.0

Tetrabenazine (milled) is combined along with Mannitol Powder,Microcrystalline Cellulose, Sodium Starch Glycolate, PVP 1(29/32 andTween 80 (Polysorbate 80) into a high shear granulator and initially drymixed at high impeller and chopper speed for 5 minutes. While mixing athigh impeller speed and low chopper speed, Purified Water is added tothe mixing powders to granulate the material. Additional mixing andwater addition with high impeller and high chopper speed continues untilthe desired granulation end-point is achieved. The resulting granulationis wet screened to break up any oversized agglomerates and the materialis added to a fluid bed drier and dried at 60° C. until the desiredL.O.D. (loss on drying) is achieved. The dried material is sievedthrough a #20 mesh screen and the oversized material is milled to aparticle size of just under 20 mesh in size. The dried and sizedmaterial is combined with Spray Dried Mannitol and Sodium StarchGlycolate into a diffusive mixer (V-Blender) where it is blended for 15minutes. Magnesium Stearate is then passed through a #30 mesh screen andadded to the blended material in the V-Blender. The contents are thenlubricated for 3 minutes and discharged for tablet compression. Using arotary tablet press fitted with punches and dies of the desired shapeand size, the lubricated blend is compressed into tablets of atheoretical weight of 125 mg.

Examples 6-8 6 mg, 12 mg, and 18 mg Tetrabenazine Gastro-ErosionalExtended Release (Small Tablet)

Table 6 discloses additional strengths of the sustained release 350 mgtablet formulation containing anti-oxidants and an aqueous film coating.

TABLE 6 mg/ mg/ mg/ Material tab % tab % tab % Tetrabenazine (milled)6.0 1.7 12.0 3.4 18.0 5.1 Mannitol Powder 191.3 54.7 186.9 53.4 180.551.6 Microcrystalline 64.2 18.3 62.6 17.9 63.0 18.0 Cellulose PVP K29/3214.0 4.0 14.0 4.0 14.0 4.0 BHA 0.5 0.1 0.5 0.1 0.5 0.1 Tween 80(Polysorbate 80) 4.0 1.1 4.0 1.1 4.0 1.1 Mannogem ® EZ (spray 31.1 8.931.1 8.9 31.1 8.9 dried mannitol) POLYOX ® N60K 35.0 10.0 35.0 10.0 35.010.0 BHT 0.4 0.1 0.4 0.1 0.4 0.1 Magnesium Stearate 3.5 1.0 3.5 1.0 3.51.0 Totals: 350.0 100.0 350.0 100.0 350.0 100.0 Core Tablets: 350.0 97.1350.0 97.1 350.0 97.1 Opadry II 85F184 22 White 10.5 2.9 10.5 2.9 10.52.9 Totals (Coated Tablets): 360.5 100.0 360.5 100.0 360.5 100.0

Tetrabenazine (milled) is combined along with Mannitol Powder,Microcrystalline Cellulose, PVP 1(29/32, BHA and Tween 80 (Polysorbate80) into a high shear granulator and initially dry mixed at highimpeller and chopper speed for 5 minutes. While mixing at high impellerspeed and low chopper speed, Purified Water is added to the mixingpowders to granulate the material. Additional mixing and water additionwith high impeller and high chopper speed continues until the desiredgranulation end-point is achieved. The resulting granulation is wetscreened to break up any oversized agglomerates and the material isadded to a fluid bed drier and dried at 60° C. until the desired L.O.D.(loss on drying) is achieved. The dried material is sieved through a #20mesh screen and the oversized material is milled to a particle size ofjust under 20 mesh in size. The dried and sized material is combinedwith Spray Dried Mannitol, BHT and POLYOX® N60K into a diffusive mixer(V-Blender) where it is blended for 15 minutes. Magnesium Stearate isthen passed through a #30 mesh screen and added to the blended materialin the V-Blender. The contents are then lubricated for 3 minutes anddischarged for tablet compression. Using a rotary tablet press fittedwith punches and dies of the desired shape and size, the lubricatedblend is compressed into tablets of a theoretical weight of 350 mg. Thetablet cores are then placed into a side vented, fully perforatedcoating pan where they are coated with a 20% solids dispersion ofOpadry® II 85F18422 White in Water until a theoretical weight gain of 3%is obtained.

The following examples may be made with varying amounts oftetrabenazine, and increasing proportionally the amount of fillermaterial. Those skilled in the art will easily be able to vary theproportions of glidants, fillers/diluents, binders, disintegrants, andother ingredients in order to optimize the formulation and its method ofmanufacture.

Example 9 8 mg and 15 mg Tetrabenazine Gastro-Erosional Extended Release(Small Tablet)

Table 7 below discloses the elements of a 350 mg total weightgastro-erosional granulation formulation tablet comprising 8 mg or 15 mgtetrabenazine, as well as optionally coated 360.5 mg total weightgastro-erosional granulation formulation tablet comprising 8 mg or 15 mgtetrabenazine.

TABLE 7 Material mg/tab % mg/tab % Tetrabenazine (milled) 8.0 2.3 15.04.3 Sodium Ascorbate 5.0 1.4 5.0 1.4 Mannitol Powder 186.9 53.4 181.751.9 Microcrystalline Cellulose 62.3 17.8 60.6 17.3 PVP K29/32 14.0 4.014.0 4.0 Tween 80 (Polysorbate 80) 3.8 1.1 3.8 1.1 Mannogem ® EZ (spraydried 31.5 9.0 31.5 9.0 mannitol) Kollidon SR 35.0 10.0 35.0 10.0Magnesium Stearate 3.5 1.0 3.5 1.0 Totals: 350.0 100.0 350.0 100.0 CoreTablets: 350.0 97.1 350.0 97.1 Opadry II 85F184 22 White 10.5 2.9 10.52.9 Totals (Coated Tablets): 360.5 100.0 360.5 100.0

Same process as described for Example 1.

From the foregoing description, one skilled in the art can ascertain theessential characteristics of this invention, and without departing fromthe spirit and scope thereof, can make various changes and modificationsof the invention to adapt it to various usages and conditions.

1. An extended-release pharmaceutical formulation comprising, in a soliddosage form for oral delivery of between about 100 mg and about 1 gtotal weight: between about 2 and about 18% of an active ingredient thatis tetrabenazine; between about 70% and about 96% of one or morediluents selected from the group consisting of mannitol powder, spraydried mannitol, microcrystalline cellulose, lactose, dicalciumphosphate, tricalcium phosphate, starch, pregelatinized starch,compressible sugars, silicified microcrystalline cellulose, and calciumcarbonate; between about 1% and about 10% of a water-soluble binderselected from the group consisting of polyvinylpyrrolidone,hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC),ethylcellulose (EC), corn starch, pregelatinized starch, gelatin, andsugar; and between about 0.5 and about 2% of a surfactant selected fromthe group consisting of polysorbate, sodium lauryl sulfate, and docusatesodium.